This invention is related to Merck case 18727IA, U.S. Ser. No. 07/991,164, filed Dec. 16, 1992, now abandoned, U.S. Ser. No. 08/148,476; and U.S. Ser. No. 08/294,771.
A retrovirus designated human immunodeficiency virus (HIV) is the etiological agent of the complex disease that includes progressive destruction of the immune system (acquired immune deficiency syndrome; AIDS) and degeneration of the central and peripheral nervous system. This virus was previously known as LAV, HTLV-III, or ARV. A common feature of retrovirus replication is reverse transcription of the RNA genome by a virally encoded reverse transcriptase to generate DNA copies of HIV sequences, a required step in viral replication. It is known that some compounds are reverse transcriptase inhibitors and are effective agents in the treatment of AIDS and similar diseases, e.g., azidothymidine or AZT.
This invention relates to an improved process for synthesizing the AIDS antiviral L-738,372, which is a chiral compound of the structure ##STR1##
The substituted quinazoline L-738,372 is an exceptionally potent inhibitor of HIV reverse transcriptase. This activity of the compound makes it useful in the treatment or prevention of AIDS.
The present invention describes an improved synthesis of an intermediate for this compound. A prior method employs a Grignard reagent, which is unsuitable for commercial scale-up. The improved process of the present invention gives higher yields, and is an entirely different approach. In this invention there is a condensation of para-chloroaniline with cyanocyclopropane to give the desired intermediate 4-chloro-2-cyclopropylcarbonylaniline. Alternatively, but less preferably, para-chloroaniline is condensed with chlorobutyronitrile, followed by a second step of ring closure to form 4-chloro-2-cyclopropylcarbonylaniline.